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Background Metastasis, the leading cause of cancer death, exhibits a highly heterogeneous and suppressive cancer microenvironment.Methods Here, we sequenced 97 matched samples by using single-cell RNA sequencing and spatial transcriptomics of colorectal cancer liver metastasis.Results Strikingly, the metastatic microenvironment underwent remarkable spatial reprogramming of immunosuppressive cells such as MRC1+ CCL18+ M2-like macrophages. We further developed scMetabolism, a computational pipeline for quantifying single-cell metabolism, and observed that those macrophages harbored enhanced amino acid metabolic activity. Interestingly, neoadjuvant chemotherapy could block this status and restore the antitumor immune balance in responsive patients, whereas the nonresponsive patients deteriorated into a more suppressive one. In parallel, metastatic cancer cells displayed the metabolic switch from OXPHOS to glycolysis, which is dependent on the metabolic master regulator LY6E.Conclusions Our work described the metabolism co-evolution of both immune and cancer cells during metastasis and uncovered the black box of how tumors respond to neoadjuvant chemotherapy.Acknowledgements This work was supported by the National Natural Science Foundation of China (no. 81961128025; to Q. Gao); National Natural Science Foundation of China (no. 91942313; to X. Huang); Program of Shanghai Academic Research Leader (no. 19XD1420700; to Q. Gao); Shanghai Municipal Key Clinical Specialty; The Strategic Priority Research Program (XDPB0303) and Frontier Science Key Research Project (QYZDB-SSW-SMC036) of Chinese Academy of Sciences (X. Zhang); and Shanghai Municipal Science and Technology Major Project (no. 2019SHZDZX02; to X. Zhang).Ethics Approval We collected samples of pathologically diagnosed CRLM from Zhongshan Hospital, Fudan University, with written informed consent and approval from the Institutional Review Board-approved protocols (B2020-348R).Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.